2.1 Esophageal Cancer
Esophageal cancer is a malignant tumor of the esophagus (the muscular tube that propels food from the mouth to the stomach). While esophageal cancer is relatively uncommon in North America, where the incidence is less than 5 out of 100,000 people, its prevalence has reached almost epidemic proportions in other areas of the world, particularly in China, Japan, Iran and South Africa. However, the number of people afflicted by esophageal cancer in the Western world has been growing steadily over the last few decades. For instance, between 1994 to 1999, the annual rate of occurrence for esophageal cancer in the United States is four to five folds of that from 1974 to 1989, during which, the annual rate of occurrence for esophageal cancer is five to six times that from 1935 to 1971.
Carcinoma of the esophagus occurs most often in men over 50 years old. The male-to-female ratio being approximately 3:1 (Garfinkel et al., 1980, CA Cancer J Clin. 30:39–44). The exact causes of esophageal cancer are not known and a variety of etiologic factors are suspected in causing esophageal cancer. Genetic factors do not appear to play a role except in individuals with the rare condition of keratosis palmaris et plantaris (tylosis), which is inherited as an autosomal dominant trait. Dietary factors may play a role because concentrations of nitrosamines and their precursors (nitrates and nitrites) are high in food and water samples from areas in China with a high incidence of esophageal cancer. Other risk factors include smoking, alcohol consumption, low socioeconomic status and a deficient diet. Barrett's esophagus, a complication of gastroesophageal reflux disease (GERD) is also a risk factor for the development of esophageal cancer.
Dysphagia is by far the most frequent complaint of patients with esophageal cancer. Difficulty swallowing solids or liquids, regurgitation of food, heartburn, vomiting blood and chest plan unrelated to eating are other common symptoms. Complications associated with esophageal cancer include severe weight loss and spread of the tumor to other parts of the body. Signs suggesting advanced stages of the disease include cervical adenopathy; chronic cough, suggesting tracheal involvement; chocking after eating, suggesting a fistula with the tracheobronchial tree; massive hemoptysis or hematemesis or both, suggesting perforation of the lesion into adjacent vascular structures; and hoarseness, suggesting recurrent pharyngeal nerve paralysis.
Diagnostic procedures often used on patients complaining of difficulty in swallowing range from the use of gallium 67 or cobalt 57 swallow, EGD (esophagogastroduodenoscopy), biopsy, chest MRI, thoracic CT (usually used to determine the stage of the disease), PET scan, and evidence of occult blood in stool. The characteristic finding of an irregular ragged mucosal pattern with luminal narrowing is typical of carcinoma of the esophagus. Unlike benign obstructing lesions, esophageal cancer is usually not associated with proximal dilatation of the esophagus.
There are two main types of esophageal cancer, squamous cell carcinoma and adenocarcinoma. At one time, squamous cell carcinoma was by far the more common of the two cancers, and was once responsible for almost 90% of all esophageal cancers. However, more recent medical studies show that squamous cell cancers make up only about two thirds of esophageal cancers today. Since the entire esophagus is normally lined with squamous cells, squamous cell carcinoma can occur anywhere along the length of the esophagus. Adenocarcinoma, on the other hand, starts in glandular tissue, which normally does not cover the esophagus and usually arise from metaplasia of Barrett's mucosa. Tumors such as adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, carcinosarcoma and pseudosarcoma that are similar in microscopic appearance to those arising in salivary glands account for most of the remaining glandular tumors of the esophagus. Sarcomas, melanoma, plasmacytoma, verrucous carcinoma and oat cell carcinoma together represent less than one percent of all malignant esophageal tumors.
The staging of esophageal cancer is based on the revised criteria of TNM staging by the American Joint Committee for Cancer (AJCC) published in 1988. Staging is the process of describing the extent to which cancer has spread from the site of its origin. It is used to assess a patient's prognosis and to determine the choice of therapy. The stage of a cancer is determined by the size and location in the body of the primary tumor, and whether it has spread to other areas of the body. Staging involves using the letters T, N and M to assess tumors by the size of the primary tumor (T); the degree to which regional lymph nodes (N) are involved; and the absence or presence of distant metastases (M)—cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Each of these categories is further classified with a number 1 through 4 to give the total stage. Once the T, N and M are determined, a “stage” of I, II, III or IV is assigned. Stage I cancers are small, localized and usually curable. Stage II and III cancers typically are locally advanced and/or have spread to local lymph nodes. Stage IV cancers usually are metastatic (have spread to distant parts of the body) and generally are considered inoperable.
Traditional treatment options include surgery to remove the tumor and all or part of the esophagus (esophagectomy), chemotherapy and radiation therapy. Surgery is a common choice at early stage tumors and will frequently cure the disease when the cancer is confined to the esophagus. However, for patients who have experienced the cancer spreading outside the esophagus (metastatic disease), cure is generally not possible, and treatment is directed towards relief of symptoms (palliative therapy). Other modalities that may be used to improve a patient's ability to swallow include endoscopic dilation of the esophagus (sometimes with placement of a stint) to open the esophagus, or photodynamic therapy.
The use of radiation therapy as a single modality in the definitive treatment of esophageal cancer has met with little success despite efforts to increase the total dose to the tumor and reduce the amount of irradiated normal tissue. The median survival for patients treated with radiation is around 12 months, and long-term survivors are few (Beatty et al., 1979, Cancer 43:2254–67; Newaishy et al., 1982, Clin Radiol. 33:347–352; Schuchman et al, 1980, J Thorac Cardiovasc Surg. 79:67–73). The best results with radiation alone have come from a series reported by Pearson, in which a 5-year survival rate of 17% was achieved after 50 Gy, 2.5 Gy per fraction (1977, Cancer 39:882–90). However, a review by Earlam and Cunha-Melo of more than 8,400 patients from 49 series concluded that the overall 1-, 2-and 5-year survival rates were 18%, 8% and 6%, respectively (1980, Br J Surg. 67:457–61). Further, since the radiation dose necessary to either radically treat or achieve palliation exceeds 40 Gy, most patients experience some degree of dysphagia.
The role of chemotherapy in the management of esophageal cancer is continually evolving. Oftentimes, chemotherapy with radiation in adjunct to surgery is used. In general, chemotherapy can achieve long-term survival rates of up to 15% to 20%, even in patients with recurrent or metastatic disease (Ali et al., 2000, Oncology 14(8):1223–30). Unfortunately, the high initial response rates to first line chemotherapy does not appear to translate into a survival benefit (Kohno and Kitahara, 2001, Gan To Kagaku Ryoho 28(4):448–53). Moreover, there are many undesirable side effects associated with chemotherapy such as temporary hair loss, mouth sores, anemia (decreased numbers of red blood cells that may cause fatigue, dizziness, and shortness of breath), leukopenia (decreased numbers of white blood cells that may lower resistance to infection), thrombocytopenia (decreased numbers of platelets that may lead to easy bleeding or bruising), and gastrointestinal symptoms like nausea, vomiting, and diarrhea. Active chemotherapeutic agents include bleomycin, cisplatin, 5-fluorouracil, mitomycin C, oxorubicin, methotrexate, paclitaxel (Taxol), and irinotecan (CPT-11, or Camptosar).
The identification of active chemotherapeutic agents against cancers traditionally involved the use of various animal models of cancer. The mouse has been one of the most informative and productive experimental system for studying carcinogenesis (Sills et al., 2001, Toxicol Letters 120:187–198), cancer therapy (Malkinson, 2001, Lung Cancer 32(3):265–279; Hoffman RM., 1999, Invest New Drugs 17(4):343–359), and cancer chemoprevention (Yun, 1999, Annals NY Acad Sci. 889:157–192). Cancer research started with transplanted tumors in animals which provided reproducible and controllable materials for investigation. Pieces of primary animal tumors, cell suspensions made from these tumors, and immortal cell lines established from these tumor cells propagate when transplanted to animals of the same species.
To transplant human cancer to an animal and to prevent its destruction by rejection, the immune system of the animal are compromised. While originally accomplished by irradiation, thymectomy, and application of steroids to eliminate acquired immunity, nude mice that are athymic congenitally have been used as recipients of a variety of human tumors (Rygaard, 1983, in 13th International Cancer Congress Part C, Biology of Cancer (2), pp37–44, Alan R. Liss, Inc., NY; Fergusson and Smith, 1987, Thorax, 42:753–758). While the athymic nude mouse model provides useful models to study a large number of human tumors in vivo, it does not develop spontaneous metastases and are not suitable for all types of tumors. Next, the severe combined immunodeficient (SCID) mice is developed in which the acquired immune system is completely disabled by a genetic mutation. Human lung cancer was first used to demonstrate the successful engraftment of a human cancer in the SCID mouse model (Reddy S., 1987, Cancer Res. 47(9):2456–2460). Subsequently, the SCID mouse model have been shown to allow disseminated metastatic growths for a number of human tumors, particularly hematologic disorders and malignant melanoma (Mueller and Reisfeld, 1991, Cancer Metastasis Rev. 10(3):193–200; Bankert et al., 2001, Trends Immunol. 22:386–393). With the recent advent of transgenic technology, the mouse genome has become the primary mammalian genetic model for the study of cancer (Resor et al., 2001, Human Molec Genet. 10:669–675).
While surgery, chemotherapeutic agents, hormone therapy, and radiation are useful in the treatment of esophageal cancer, there is a continued need to find better treatment modalities and approaches to manage the disease that are more effective and less toxic, especially when clinical oncologists are giving increased attention to the quality of life of cancer patients. The present invention provides an alternative approach to cancer therapy and management of the disease by using an oral composition comprising yeasts.
2.2 Yeast-Based Compositions
Yeasts and components thereof have been developed to be used as dietary supplement or pharmaceuticals. However, none of the prior methods uses yeast cells which have been cultured in an electromagnetic field to produce a product that has an anti-cancer effect. The following are some examples of prior uses of yeast cells and components thereof:
U.S. Pat. No. 6,197,295 discloses a selenium-enriched dried yeast product which can be used as dietary supplement. The yeast strain Saccharomyces boulardii sequela PY 31 (ATCC 74366) is cultured in the presence of selenium salts and contains 300 to about 6,000 ppm intracellular selenium. Methods for reducing tumor cell growth by administration of the selenium yeast product in combination with chemotherapeutic agents is also disclosed.
U.S. Pat. No. 6,143,731 discloses a dietary additive containing whole β-glucans derived from yeast, which when administered to animals and humans, provide a source of fiber in the diet, a fecal bulking agent, a source of short chain fatty acids, reduce cholesterol and LDL, and raises HDL levels.
U.S. Pat. No. 5,504,079 discloses a method of stimulating an immune response in a subject utilizing modified yeast glucans which have enhanced immunobiologic activity. The modified glucans are prepared from the cell wall of Saccharomyces yeasts, and can be administered in a variety of routes including, for example, the oral, intravenous, subcutaneous, topical, and intranasal route.
U.S. Pat. No. 4,348,483 discloses a process for preparing a chromium yeast product which has a high intracellular chromium content. The process comprises allowing the yeast cells to absorb chromium under a controlled acidic pH and, thereafter inducing the yeast cells to grow by adding nutrients. The yeast cells are dried and used as a dietary supplement.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.